Superoxide dismutases catalyze the decomposition of the cytotoxic superoxide free radical, and are the primary enzymatic defense against oxygen toxicity. Two classes of dismutases are known, those which contain both copper and zinc, and those which contain either manganese or iron as the catalytic metal. The classes also differ in subunit size, amino acid composition, and other molecular properties. The objective of the proposed research is to clarify current concepts about structural, functional, and evolutionary relationships between these two classes. The copper-zinc dismutase from baker's yeast and the manganese dismutase from chicken liver mitochondria will be studied by chemical modification studies, for specific modification of functional residues and for general assessment of topology, and by complete amino acid sequence analysis. These properties will be compared with those of the previously characterized bovine erythrocyte copper-zinc and E. coli manganese dismutases, to deduce similarity in metal binding site and overall surface topology, to evaluate rigorously the present hypothesis of independent evolution for the two classes, and to assess the present limited sequence data of prokaryote and mitochondrial dismutase homologies which support the endosymbiotic hypothesis of mitochondrial origin. This information about dismutase structure, function, and evolution will be useful for optimizing current applications of superoxide dismutases in treatment of veterinary inflammations and in current clinical trials in radiation cystitis and degenerative joint disease.